978TiP - Durvalumab with cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: A phase I/II trial

Background

Cisplatin-based, concurrent chemo-radiation (CRT) is the established standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC). In view of its well-known prohibitive toxicity, CRT is far from being a desirable strategy. The combination of cetuximab (CTX) and radiotherapy (RT) was shown to be significantly inferior to CRT in the HPV-positive population by two large phase III randomized trials, but it represents a validated treatment option for platinum unsuitable patients. For the still prevalent HPV-negative population and the high risk-HPV positive disease, there is an unmet need for alternative treatment paradigms. The efficacy of immune checkpoint inhibitors in the context of recurrent/metastatic disease anticipated the possible integration of immunotherapy into the curative setting. Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody. Potentially, the inhibition of the PD-1/PD-L1 checkpoint may synergize with both CTX and RT through immunologic interplay, aiming to reverse the HNSCC-induced immune suppression. The DUCRO study will seek to demonstrate if such a strategy may be safe and active.

Trial design

In this open label, multi-center, single-arm, phase I/II study, enrolled patients will receive RT (69.9 Gy/2.12 Gy in 33 fractions) with concurrent CTX (400 mg/m²1 week before RT start followed by 250 mg/m² weekly) and DUR (fixed dose of 1500 mg every 4 weeks starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). Assuming a 2-year PFS of 66% based on historical data from RTOG study 0129, the experimental regimen is hypothesized to yield a 12% absolute increase at 2 years, corresponding to a hazard ratio of 0.6 (α = 0.1, power is 0.80 when the 2-year PFS is 78%). The required sample size with this design is 69 patients. Asafety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk (≥N2a or ≥T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx (≥T2, ≥N2b, ≥10 pack/years; all staged with TNM 7^thedition) will be eligible. The trial is ongoing (FPI: July 2019).

Clinical trial identification

Eudra: 2016-004668-20 CT; NCT03051906.

Editorial acknowledgement

Legal entity responsible for the study

Lorenzo Livi.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.